Faster Drug Approvals Linked to Increased Safety Issues

Larry Hand

August 13, 2014

As the US Food and Drug Administration (FDA) has accelerated its drug-approval process since 1992, the rate of black box warnings on prescription drugs, as well drug withdrawals, has increased, according to an article published in the August issue of Health Affairs.

Cassie Frank, MD, an instructor of medicine at Cambridge Health Alliance in Massachusetts and at Harvard Medical School, Boston, Massachusetts, and colleagues analyzed the history of 748 new molecular entities approved by the FDA between 1975 and 2009.

They compared the records of drugs approved before and after the 1992 enactment of the Prescription Drug User Fee Act (PDUFA), which allowed the FDA to collect fees from pharmaceutical companies to pay for resources needed to accelerate the drug-approval process. PDUFA has been renewed 4 times since 1992.

Of the 748 new molecular entities approved for the entire period, 114 (15.2%) had received 1 or more black box warnings and 32 (4.3%) were withdrawn from the market for safety reasons. In total, label changes for all black box warnings plus withdrawals came to 208 (27.8%). Half of the warnings were issued within 12 years of approval, and half of the withdrawals occurred within 5 years of approval.

The researchers found that drugs approved after enactment of PDUFA were more likely to be withdrawn or to receive a black box warning, with a rate of warning or withdrawal of 21.2 per 100 drugs before PDUFA and 26.7 per 100 after PDUFA (odds ratio [OR], 1.35; P < .05).

The authors point out, however, that they were unable to establish causality.

"New drugs have a one-in-three chance of acquiring a new black-box warning or being withdrawn for safety reasons within twenty-five years of approval," the researchers conclude. "We believe that the ultimate solution is stronger US drug approval standards. In the interim, with the rare exception of truly breakthrough therapies, doctors should preferentially prescribe drugs that have been on the market longer and hence have a more established track record of safety."

FDA, Industry Counter Findings

The FDA issued a 2-paragraph statement in response to the article: "PDUFA has enhanced pre-market review and created a modern post-market drug safety system that follows products across their full life cycle. Specifically, PDUFA provides FDA revenue to hire additional reviewers and support staff and upgrade its information technology systems to maximize the efficiency of the application review process for new drugs and biological products without compromising FDA's high standards for approval.

"Additionally, PDUFA funding has helped the FDA modernize and transform the post-market drug safety surveillance system. It has helped ensure the safety of drugs after they are approved for as long as they remain on the market and have increased FDA's drug safety surveillance capacity. FDA has been able to adopt new scientific approaches and improve the utility of existing tools for the detection and prevention of adverse events, including obtaining access to the best available databases to better analyze drug safety signals."

Similarly, Robert Zirkelbach, senior vice president of communications Pharmaceutical Research and Manufacturers of America, emphasized the benefits of the updated system. "Prior to 1992, the drug review process was unpredictable, lagging behind other countries and stalling patient access to critical new medicines," he said in a news release. "Providing the FDA with stable, consistent funding, PDUFA revolutionized the [drug review] process and strengthened the agency's high safety and efficacy standards."

He continued, "Since its enactment in 1992, PDUFA has sped up patient access to over 1,500 new medicines, including treatments combatting some of our nation's most deadly diseases. By injecting greater consistency, transparency, and predictability into the drug review process, PDUFA has played a crucial role in improving public health."

Interim Measures

To improve patient safety, the authors mention several measures that could be adopted in individual clinics or in the community at large:

  • Physicians and patients could consider whether a new drug is a breakthrough therapy and, if not, consider alternatives.

  • The community could require inclusion information or a symbol in labels and marketing statements to identify newly approved drugs.

  • The FDA could focus more on postmarketing surveillance.

"Doctors need to know in real terms, Is this a breakthrough drug or not?" coauthor Sidney M. Wolfe, MD, founder and senior adviser at the Health Research Group, Public Citizen, Washington, DC, told Medscape Medical News. "Drugs that really have a clinical advantage should be given higher priority, and there are a bunch of pathways including accelerated approval and breakthrough drugs, as long as you don't break the rules and slight on either the efficacy or the safety."

However, he added, the "overwhelming majority" of drugs approved during the period were not breakthrough drugs. "It's hard to identify any breakthrough drugs at all."

Drugs taken off the market before PDUFA "had an average review time for submission and approval of 3 years. The ones that were taken off after had an average review time of 1 year," Dr. Wolfe said. "That was certainly one of the purposes of PDUFA, but the failure to really treat these 2 groups of drugs [breakthrough and nonbreakthrough] differently is what the problem is."

Where to Look?

A side result of the study was the finding that there is a lack of single-source information on black box warnings and withdrawals.

"I would recommend that doctors and other prescribers rely on a source other than the print version of the Physicians' Desk Reference for comprehensive drug label information," lead author Dr. Frank told Medscape Medical News. "I can't recommend a specific source, since we didn't compare different sources in this study. It is, however, remarkable that no comprehensive source of information on black box warnings or withdrawals is available to clinicians, researchers, or the public."

She summed up her view of the overall findings: "I'd like to say that the primary mission of the FDA is to ensure patients' safety. Our study raises concerns about how well the FDA is doing this. The FDA needs to make sure drugs are safe before they're approved, not rush to judgement in order to meet artificial deadlines. In the meantime, doctors and patients should avoid new drugs, especially when older, safer drugs are available."

The authors have disclosed no relevant financial relationships.

Health Aff. 2014;33:1453-1459. Abstract


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